Kuhn_2025_Drug.Metab.Dispos_53_100111

CYP1A2 is involved in the metabolism of many drugs and environmental chemicals and is induced by polycyclic hydrocarbons in tobacco smoke and charcoal-broiled meat. Using 103 histologically tumor-free human liver samples, we determined the effect of 5 CYP1A2 mutations versus other factors on CYP1A2 expression and activity. We genotyped 100 liver samples by polymerase chain reaction amplification and restriction fragment length polymorphism analysis. CYP1A2 protein expression was assessed using immunohistochemistry, ELISA, and western blot analyses, and enzyme activities were measured using 3 monooxygenase model reactions for CYP1A2. Of the 100 genotyped liver samples, 4 were heterozygous for the CYP1A21C or the CYP1A21E mutation. For the CYP1A21F mutation, 57 liver samples were heterozygous and 38 were homozygous. No -729C>T or CYP1A211 mutations were found. Enzyme activities were elevated in the few livers heterozygous for the CYP1A21E mutation. Although smokers had higher CYP1A2 expression overall, enzyme activities were elevated only in smokers with the homozygous mutant CYP1A21F genotype. CYP1A2 expression and enzyme activities correlated strongly with each other. We also found a positive association between enzyme expression/activities and serum albumin and cholinesterase levels but a negative correlation with body mass index, blood glucose concentration, serum levels of C-reactive protein and fibrinogen, as well as with the degree of liver steatosis, inflammatory infiltration, and fibrosis. Thus, our results demonstrate that the CYP1A2 genotype affects CYP1A2 expression and activities, as do lifestyle factors and inflammatory processes. SIGNIFICANCE STATEMENT: Using a panel of 103 histologically tumor-free human liver samples, we were able to show an impact of genetic and lifestyle factors such as tobacco smoking, nutritional status, inflammatory conditions, and the extent of liver damage on CYP1A2 enzyme expression and activities. The contribution of each parameter, however, was only low to moderate. Therefore, other, still unknown factors must be involved in the large interindividual variability observed in this enzyme.